Introduction In 2020, the world experienced the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as the coronavirus disease 2019 (COVID-19) pandemic. Mounting evidence indicates that the gut microbiome plays a role in host immune response to infections and, in turn, may have an impact on the disease trajectory of SARS-CoV2 infection. However, it remains to be established whether modulation of the microbiome can impact COVID-19-related symptomatology and patient outcomes. Therefore, we conducted a study designed to modulate the microbiome evaluating the safety and physiologic effects of KB109 combined with self-supportive care (SSC) vs SSC alone in non-hospitalized patients with mild to moderate COVID-19. KB109 is a novel synthetic glycan developed to increase the production of gut microbial metabolites that support immune system homeostasis through gut microbiome modulation. Our goal was to gain a better understanding of the safety of KB109, the natural course of COVID-19 symptomatology, and the possible role of the gut microbiome in patients with mild to moderate COVID-19. Methods Adult patients who tested positive for COVID-19 were randomized 1:1 to receive KB109 combined with SSC or SSC alone for 14 days and were then followed for an additional 21 days (35 days in total). Patients self-assessed their COVID-19-related symptoms (8 cardinal symptoms plus 5 additional symptoms) and self-reported comorbidities. The primary and secondary objectives were to evaluate the safety of KB109 plus SSC compared with that of SSC alone and to evaluate selected measures of health, respectively. Results Between July 2, 2020 and December 23, 2020, 350 patients were randomized to receive KB109 and SSC (n=174) or SSC alone (n=176). Overall, the most common comorbidities reported were hypertension (18.0% [63/350 patients]) followed by chronic lung disease (8.6% 30/350 patients). KB109 was well tolerated with most treatment-emergent adverse events being mild to moderate in severity. The administration of KB109 plus SSC reduced medically-attended visits (ie, hospitalization, emergency room visits, or urgent care visits) by 50.0% in the overall population and by 61.7% in patients with [≥]1 comorbidity; in patients aged [≥]45 years or with [≥]1 comorbidity, medically-attended visits were reduced by 52.8%, In the SSC group, patients reporting [≥]1 comorbidity had a longer median time to resolution of symptoms than those who reported no comorbidities at baseline (13 overall symptoms: 30 vs 21 days, respectively; hazard ratio [HR]=1.163 [95% CI, 0.723-1.872]; 8 cardinal symptoms: 21 vs 15 days, respectively; HR=1.283 [95% CI, 0.809-2.035]). In patients reporting [≥]1 comorbidity, median time to resolution of symptoms was shorter in the KB109 plus SSC group compared with the SSC alone group (13 overall symptoms: 30 vs 21 days, respectively; HR=1.422 [95% CI, 0.898-2.250]; 8 cardinal symptoms: 17 vs 21 days, respectively; HR=1.574 [95% CI, 0.997-2.485]). In the KB109 plus SSC group, patients aged [≥]45 years or with [≥]1 comorbidity had a shorter median time to resolution of symptoms compared with SSC alone (overall 13 symptoms: 21 vs 31 days; HR=1.597 [95% CI, 1.064-2.398]). Conclusions Results from our study show that KB109 is well tolerated among patients with mild to moderate COVID-19. Patients with [≥]1 comorbidity had a longer duration of COVID-19 symptoms than those without comorbidities. Moreover, in patients reporting [≥]1 comorbidity or aged [≥]45 years (at-risk population), administration of KB109 plus SSC improved median time to resolution of COVID-19-related symptoms and reduced the rate of medically-attended visits compared with SSC alone.

Abstract Background The prevention and treatment of bacterial infections is a human health challenge. A disadvantage of antibiotics is that they often kill beneficial commensal, bacteria in addition to, pathogenic bacteria. Indiscriminate killing disrupts the homeostasis between commensal bacteria and the host gut epithelium allowing colonization of the gut by pathogenic bacteria and increases susceptibility to infections. This research was done to develop a non-antibiotic modality to prevent bacterial infections by growing, rather than killing, commensal bacteria in the gut. Gut commensal bacteria grown on carbohydrates produce short-chain fatty acids (SCFAs) that support gut homeostasis maintenance and promote resistance to bacterial colonization. SCFAs have direct and indirect effects on the gut and lung mucosal immune system. They have also been linked to respiratory viral infection reduction and shown to influence macrophage function to mitigate pro-inflammatory neutrophil-mediated tissue damage. Methods A library of over 1,500 synthetic proprietary glycans, termed Microbiome Metabolic Therapies (MMT™), was synthesized using different chemical and enzymatic approaches. An ex vivo platform using fecal bacterial communities from human subjects was devised to screen MMTs for their abilities to deplete pathogenic bacteria, and modulate multiple aspects of bacterial metabolism. Results KB109 was identified based on its ability to reduce the relative abundance of a diversity of pathogens including clinically relevant Gram-negative and Gram-positive bacteria in human fecal communities. KB109 also increased the relative abundance of prevalent commensal bacteria. Monoculture experiments demonstrated that KB109 promotes the growth of commensal bacteria, but not pathogens. Ex vivo screening revealed that KB109 consistently increased SFCA production across multiple fecal communities. Conclusion KB109 represents an appealing activity profile and offers an opportunity to prevent enteric and systemic bacterial infections by promoting gut homeostasis and colonization resistance, and ameliorating respiratory viral infections by stimulating immune homeostasis. KB109 is under evaluation in two COVID-19 clinical studies. Disclosures Jeffrey Meisner, PhD, Kaleido Biosciences (Employee, Shareholder) Jackson Lee, PhD, Kaleido Biosciences (Employee, Shareholder) Jonathan Lawrence, PhD, Kaleido Biosciences (Employee, Shareholder) Megan Roed, BA, Kaleido Biosciences (Employee, Shareholder) Johan van Hylckama Vlieg, PhD, Kaleido Biosciences (Employee, Shareholder)

Key building blocks for the production of fully synthetic macrolides have been scaled-up in first time pilot plant and kilo-lab campaigns. These building blocks have supported the discovery of new macrolide antibiotics as well as ongoing preclinical studies.

The emergence and spread of multidrug-resistant (MDR) Gram negative bacteria presents a serious threat for public health. Novel antimicrobials that could overcome the resistance problems are urgently needed. UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) is a cytosolic zinc-based deacetylase that catalyzes the first committed step in the biosynthesis of lipid A, which is essential for the survival of Gram-negative bacteria. Our efforts toward the discovery of novel LpxC inhibitors are presented herein.

The neoclerodane diterpene salvinorin A (1) was isolated in 1982 from the rare mint SalVia diVinorum, indigenous to Oaxaca, Mexico.1 Recent efforts established salvinorin A as a potent and selective κ opioid receptor agonist, the only non-alkaloid psychoactive substance, and the most potent naturally occurring hallucinogen.2 As a result of its therapeutic potential, renewed isolation efforts have discovered a number of related salvinorin congeners,3 and a number of analogues of 1 have been prepared by semisynthesis to probe the pharmacophore and mode of binding.4 This communication describes the first synthesis of this natural product. Construction of the tricyclic salvinorin core is predicated on the proposed transannular5 Michael reaction cascade6 of bisenone macrocycle 3 (Scheme 1). Conformational analysis7 of 3 leads to a prediction wherein the resident stereocenters at C2, C4, and C12 should mutually reinforce the desired stereochemical course of the reaction. This plan permits the convergent assembly of vinyl iodide 4 and aldehyde 5, which can be prepared through established methods. The synthesis of aldehyde 5 began with the Ni(II)-(R)-BINAPcatalyzed orthoester alkylation8 of thiazolidinethione 6, followed by a subsequent Claisen condensation with ethyl hydrogen malonate9 to give â-ketoester 7 (Scheme 2). Selective formation of the (Z)-enol phosphate permitted an Fe-catalyzed cross-coupling with methylmagnesium chloride10 to furnish trisubstituted olefin 8. Reduction to the unsaturated aldehyde then allowed a selective aldol addition of acetate-derived chiral auxiliary 9.11,12 The derived allylic alcohol was protected as the tert-butyldimethylsilyl (TBS) ether 10. After revealing the terminal aldehyde, an (-)-N-methylephedrine-mediated zinc acetylide addition13 provided propargylic alcohol 11 in good diastereoselectivity. Alcohol protection as the BOM ether was uniquely effected using NaHMDS and BOMCl at low temperature under Barbier conditions.14 Semi-hydrogenation, dihydroxylation,15 and oxidative cleavage furnished fragment 5. The synthesis of vinyl iodide 4 employed an asymmetric reduction of ketone 12 using (R)-B-Me-oxazaborolidene as catalyst16 to afford alcohol 13 (Scheme 3). Alkyne isomerization17 of 13 to 14 preceded carboalumination18 and TES-silyl ether protection. In the coupling event, chelate-controlled addition of the Grignard reagent derived from 4 to aldehyde 5 afforded allylic alcohol 15 (Scheme 4). A series of protecting group manipulations provided seco-acid 16; subsequent macrolactonization using the Shiina procedure,19 desilylation, and oxidation afforded macrocycle 3. Treatment of â-ketolactone 3 with TBAF at -78 °C and warming to 5 °C induced the selective transannular reaction cascade to afford tricycle 2 as a single diastereomer. The reaction delivers two quaternary methyl stereocenters at C5 and C9 in a 1,3-diaxial alignment from the corresponding â,â-disubstituted enones, moieties known to possess poor reactivity toward conjugate addition. To complete the synthesis, we employed a deoxygenation sequence involving enol triflate formation,20 palladium-catalyzed triflate reduction,21 and subsequent conjugate reduction22 to yield 17, epimeric at C8. Protonation from the R-face by t-BuOH in situ appears to be under kinetic as well as thermodynamic control, as epimerization studies conducted on 1 (DBU, 110 °C in toluene) result in a mixture of C8-epimers biased toward 8-epi-salvinorin A 19.23 Deprotection of both the C2 and C4 acetals in 17 followed by oxidation and esterification gave 8-epi-salvinorin B (18). Epimerization using K2CO3 in oxygen-free methanol followed by acylation produced salvinorin A (1), spectroscopically identical to previous Scheme 1. Synthesis Plan for Salvinorin A (1)

Salvinorin A is a neoclerodane diterpene isolated from Salvia divinorum. As a potent agonist of the κ opioid receptor, it is the only non-alkaloid psychoactive substance and the most potent naturally occuring hallucinogen. The synthesis of salvinorin exploits a bis-Michael addition of macrocylce E to create the tricyclic core. A rich array of innovative chemistry was used to synthesise fragment B.

The stereoselective synthesis of salvinorin A is described. A macrocyclic bis-Michael reaction cascade provides the requisite tricyclic skeleton as a single diastereomer.

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